Scabies is a neglected, globally prevalent, highly contagious skin disease that affects humans and domestic and wild mammals and causes significant morbidity. It is a major health problem often associated with low- income populations and prevalence has been reported to be high in some populations of some countries where the disease may affect more than half of women and children. In developed countries, the disease shows no socioeconomic preference and affects 1-10% of the general population while it more commonly occurs in extended care facilities and prisons. In the United States and Europe, sporadic outbreaks occur in daycare centers, schools, work environments, the military, hostels, and among college students where there is much physical contact between individuals. However, the disease is often misdiagnosed and inappropriately treated and treatment failures due to acaricide resistance, toxicity of acaricides and noncompliance in their use are significant problems. Therefore, new drugs and new approaches for the prevention, diagnosis, and treatment of this old disease are needed for susceptible populations. The parasite's ability to modulate the host's immune and inflammatory responses is a critical factor that allows the parasite/species to survive. We have identified at least six mechanisms that this parasite uses to protect itself from the host's inflammatory and immune defense systems until it gets established in the host. These important insights now position us to move forward to (1) identify and characterize molecules from S. scabiei that are responsible for depressing the inflammatory and immune reactions in the host skin (and possibly disrupting the signaling pathways used by the host's cells); (2) identify species-specific antigenic molecules from scabies mites that could be used to develop new diagnostic methods (e.g., blood tests); and (3) produce recombinant molecules that possess immune-modulating activities, that could be used in a vaccine to protect against scabies, and that are scabies species-specific for use in the development of new diagnostic tests. We will accomplish these goals by a comprehensive proteomic analysis (using MALDI- TOF/TOF MS and other appropriate technologies) of the scabies mite proteome; by constructing and screening a scabies cDNA library; and by testing selected scabies mite proteins (both those isolated from mite extracts and expressed as recombinant proteins) for their ability to modulate the innate immune response of cultured skin cells and/or to be recognized by antibodies in the serum of scabies-infested hosts. Characterization and production of these important molecules will identify new targets for intervention and lead to the development of novel strategies for the diagnosis, treatment, and prevention of this disease.